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Method of producing pharmaceutical compositions comprising immunogenic chikungunya virus chikv-delta5nsp3

Active Publication Date: 2021-10-21
VALNEVA SE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The text is about a vaccine against Chikungunya virus that is currently in development. One of the most advanced vaccine candidates is a chimeric construct in a measles virus platform. The vaccine is delivered in two doses and a one-shot vaccine would be a distinct advantage in the field.

Problems solved by technology

Currently no vaccines or medications are available for the prevention or treatment of Chikungunya virus disease.

Method used

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  • Method of producing pharmaceutical compositions comprising immunogenic chikungunya virus chikv-delta5nsp3
  • Method of producing pharmaceutical compositions comprising immunogenic chikungunya virus chikv-delta5nsp3
  • Method of producing pharmaceutical compositions comprising immunogenic chikungunya virus chikv-delta5nsp3

Examples

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example 1

rials for CHIKV-Δ5nsP3 Drug Substance (DS) Production

[0056]Assembly of Synthesized CHIKV-Δ5nsP3 Genome

[0057]The CHIKV-Δ5nsP3 virus genome was synthesized in five fragments at MWG Eurofins (Germany) and was fully assembled in the pMA plasmid (pMX vector with ampicillin resistance), a standard cloning vector. The pMX vector backbone is shown in FIG. 1. All cloning and plasmid preparation procedures were carried out under TSE-free conditions using electro-competent NEB1013 E. coli cells. The cloning strategy used for the full assembly of the CHIKV-Δ5nsP3 genome in pMA is outlined in FIG. 3B. Briefly, the pMA plasmid containing fragment 1, which covers nsP1 and part of nsP2 (as shown in FIG. 3A), was linearized via EcoRI / PacI restriction digestion and fragment 2 covering parts of nsP2 and nsP3 was fused to fragment 1. In parallel, fragment 3 (covering nsP4 and C) was fused to fragment 4 (covering C and E2) via ClaI / PacI cloning. In a third cloning step, fragments 3 and 4 were cloned via...

example 2

Sequence Heterogeneities of CHIKV-Δ5nsP3 which Affect Immunogenicity

[0069]Due to the observed reduction / loss of immunogenicity (neutralizing antibody titer) and decreased plaque size at higher CHIKV-Δ5nsP3 passages, it was of interest to analyze possible sequence heterogeneities within the viral populations at different passage numbers. In addition, it was of interest to analyze the sequence of individual plaques of the viral population. Unpassaged CHIKV-Δ5nsP3 (P0) did not show sequence heterogeneities based on Sanger sequencing. In general, with increased passage numbers an increase in sequence heterogeneities for all 3 replicates was observed (Replicates A, B and C; Table 3). In the case of passaging replicate C at passage 8 (P8C), the virus population was still heterogeneous (sequence heterogeneities shown in Table 3), whereas the P15C passage showed a more homogenous virus population with defined point mutations (indicated by *). The immunogenicity data shown in FIG. 4C (Exampl...

example 3

Sequence Heterogeneities and Immunogenicity of CHIKV-Δ5nsP3 at Passage P3

[0080]The occurrence at later passages of sequence heterogeneities with adverse effects on the immunogenicity of CHIKV-Δ5nsP3 as measured by neutralizing antibody titers warranted finding the optimal passage which was characterized by both high immunogenicity as well as a viral titer sufficient for production of an effective vaccine.

[0081]To determine genetic stability of the CHIKV-Δ5nsP3 during MVSB (P1), WVSB (P2) and CHIKV-Δ5nsP3 drug substance (“VLA1553”) (P3) production, independently generated passages 1, 2 and 3 were sequenced. As determined by Sanger sequencing, P0 (virus rescue), P1 (MVSB) and P2 (WVSB) did not show any obvious sequence heterogeneities. The next step was to demonstrate reproducibility of genetic stability of P3 derived purified drug substance (DS) using P2 (WVSB) for infection. In total, four independent P3 harvests, consisting of combined day 1 and day 2 harvests, were produced in two...

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Abstract

The present invention relates to a process for producing an immunogenic live attenuated Chikungunya virus, as well as pharmaceutical compositions comprising the same.

Description

FIELD OF THE INVENTION[0001]The invention relates to a process for producing an immunogenic live attenuated Chikungunya virus, as well as pharmaceutical compositions comprising the same.BACKGROUND OF THE INVENTION[0002]Chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus from the genus Alphavirus, family Togaviridae. Chikungunya virus disease is mainly an outbreak disease and is associated with high attack rates. The virus is transmitted to humans via a mosquito vector and causes fever, rash, fatigue and severe polyarthralgia. Infections with CHIKV generally resolve spontaneously and are not usually fatal, except in rare cases involving CNS infection, where the death rate is between 10 to 30 percent. Particularly at risk for CHIKV CNS disease are infants under one year and adults over 65 years, with an infection rate 25-fold and 6-fold higher than the general population, respectively. The rate of persistent disabilities in children following CHIKV encephalitis is...

Claims

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Application Information

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IPC IPC(8): A61K39/12C12N7/00C07K14/005A61K9/00A61K9/19A61P31/14
CPCA61K39/12C12N7/00C07K14/005A61K9/0019A61K9/19A61K2039/5254C12N2770/36122C12N2770/36121C12N2770/36123C12N2770/36134A61P31/14Y02A50/30A61K2039/54
Inventor FRITZER, ANDREAMEINKE, ANDREASLUNBERG, URBANNEBENFUHR, MARIOHEINDL-WRUSS, JURGENSCHLEGL, ROBERTLEON, ARNAUD
Owner VALNEVA SE
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